The goal of this application is to further our understanding of the role of synaptic plasticity of glutamate synapses on dopamine neurons in long-term modifications of the brain that occur with drugs of abuse. Our hypothesis is that excitatory synapses in the dopaminergic reward pathway are pathologically activated in the presence of highly addictive substances such as amphetamine and opiates, and that this activation represents an early cellular contribution to the development of addiction. Over the past three years, my laboratory has used the brain slice preparation to study cellular mechanisms of synaptic depression in the ventral tegmental area (VTA), a region necessary for the development of addictive behaviors. We have found support for our hypothesis that drugs of abuse interact with synaptic plasticity, as amphetamine entirely abolishes long-term depression at glutamatergic synapses. The block of this form of synaptic plasticity is analogous to the removal of a normal brake on excitation of the dopamine system; the long-term block induced by amphetamine continuously present for long periods of time is expected to promote abnormally enhanced firing of dopamine neurons, a cellular response characteristic of the great majority of addictive substances likely to promote the development of addiction. Further examination of the mechanisms normally underlying long-term synaptic depression and the mechanisms by which amphetamine interferes with this plasticity is an important area for further research. However, before embarking on more detailed work at the cellular level, I have increasingly felt it is necessary to verify our work in the intact brain. To date no one has examined synaptic plasticity at excitatory synapses in the VTA in vivo. Thus, it is not known whether long-term depression occurs here in the intact brain, nor whether amphetamine blocks tong-term depression. The purpose of this small grant application is to allow my lab to use an entirely new technique for us, in vivo recordings from the VTA, to verify our basic in vitro findings. We expect that the proposed studies will confirm our in vitro work, and provide important new leads to use in that work.